Stability of siRNA polyplexes from poly(ethylenimine) and poly(ethylenimine)-g-poly(ethylene glycol) under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and Single Photon Emission Computed Tomography (SPECT) imaging

Merkel, Olivia M.; Librizzi, Damiano; Pfestroff, Andreas; Schurrat, Tino; Buyens, Kevin; Sanders, Niek N.; Smedt, Stefaan C. De; Béhé, Martin; Kissel, Thomas

doi:10.1016/j.jconrel.2009.05.016

Cited by 170 publications

(161 citation statements)

References 53 publications

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“…Like most cationic polymer-based siRNA delivery systems (5)(6)(7)(8)(9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10)(11)(12). In fact, polymer complexation often does not extend the circulation time of siRNA.…”

Section: Pharmacokinetics | Glomerulusmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

305

266

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Despite being engineered to avoid renal clearance, many cationic polymer (polycation)-based siRNA nanoparticles that are used for systemic delivery are rapidly eliminated from the circulation. Here, we show that a component of the renal filtration barrier-the glomerular basement membrane (GBM)-can disassemble cationic cyclodextrin-containing polymer (CDP)-based siRNA nanoparticles and, thereby, facilitate their rapid elimination from circulation. Using confocal and electron microscopies, positron emission tomography, and compartment modeling, we demonstrate that siRNA nanoparticles, but not free siRNA, accumulate and disassemble in the GBM. We also confirm that the siRNA nanoparticles do not disassemble in blood plasma in vitro and in vivo. This clearance mechanism may affect any nanoparticles that assemble primarily by electrostatic interactions between cationic delivery components and anionic nucleic acids (or other therapeutic entities). pharmacokinetics | glomerulusA major challenge with the use of small interfering RNA (siRNA) in mammals is their delivery to intracellular locations in specific tissues (1). The two most investigated approaches to siRNA delivery involve the combination of siRNA with cationic lipids (lipoplexes, liposomes, micelles) or cationic polymers (polyplexes) (2). Polymer-based siRNA delivery vehicles can be tuned to be nonimmunogenic, nononcogenic, nontoxic, and targeted (3). A targeted nanoparticle formulation of siRNA (not chemically modified) with a cationic, cyclodextrin-containing polymer (CDP)-based delivery vehicle (clinical version denoted CALAA-01) was shown to accumulate in human tumors and deliver functional siRNA from a systemic, i.v. infusion (4). This first-in-human study demonstrated the clinical potential for cationic polymerbased siRNA delivery systems.Like most cationic polymer-based siRNA delivery systems (5-9), the siRNA/CDP nanoparticle is rapidly eliminated from circulation (shown in mice, monkeys, and humans) (10-12). In fact, polymer complexation often does not extend the circulation time of siRNA. The rapid clearance of these siRNA nanoparticles is puzzling because they are engineered to be above the size cutoff for single-pass clearance via renal filtration (13). In understanding the mechanism behind the rapid clearance of this type of cancer therapeutic, we can efficiently seek ways to increase their circulation time and, thus, enhance their anticancer efficacy (3).We hypothesize that the paradoxical renal clearance of polycation-nucleic acid nanoparticles results from their binding and disassembly by components of the renal filtration barrier. Three key properties of such nanoparticles (diameters between 10 and 100 nm, positive zeta potentials, and electrostatically driven selfassembly) make them susceptible to this mechanism of clearance.The renal filtration barrier, located within the glomerulus of the nephron, consists of three layers that must be traversed to enter the urinary space. These three layers are the glomerular endothelial fenestrations (≈100 n...

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Section: Pharmacokinetics | Glomerulusmentioning

confidence: 99%

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Zuckerman

Choi²,

Han³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

305

266

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“…Challenges to efficient delivery include nanoparticle dissociation via serum proteins (10,11), cellular uptake (12), endosomal escape (13), and appropriate intracellular disassembly (14,15). To address some of these challenges, single-parameter studies that evaluate the effect of chemical structure on a single biological property or on delivery performance have been carried out (16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

136

109

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Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK a , LNP stability, and cell uptake as a collective may serve as a useful prescreening tool for the advancement of LNPs in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. For the LNPs used in this work, the evaluation of multiple parameters enabled the identification of LNP pK a as one of the key determinants of LNP function and activity both in vitro and in vivo. It is anticipated that this type of analysis can aid in the identification of meaningful structure-functionactivity relationships, improve the in vitro screening process of nanoparticles before in vivo use, and facilitate the future design of potent nanocarriers.RNAi | thiol-yne | gene silencing | drug carrier

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“…The circulatory half-life of these HFDM-formulated particles (T 1/2 lz440 h, Figure 4a) was also found to be much longer than other formulations such as galactosylated cationic liposomes (T 1/2 lzo1 h) 23 or PEGylated polyplexes (T 1/2 lz¼1.5 h). 29 Using these HFDM-formulated particles, we demonstrated a 50% knockdown of the GFP target gene in tumours after systemic administration. This level of knockdown is comparable to many other studies using similar dosage, 5,30,31 although some have reported higher gene-silencing efficiency.…”

Section: Introductionmentioning

confidence: 93%

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

Singhania

Burgess

et al. 2010

Gene Ther

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Small interfering RNA (siRNA) shows great promise in cancer therapy, but its effectiveness in vivo still remains a crucial issue for its transition into the clinics. Although the successful use of polyethylene glycol (PEG)ylated lipidic delivery systems have already been reported, most of the formulation procedures used are labour intensive and also result in unstable end products. We have previously developed a simple yet efficient hydration-of-freeze-dried-matrix (HFDM) method to entrap siRNA within lipid particles, in which the products exhibited superior stability. Here, we show that these HFDM-formulated particles are stable in the presence of serum and can deliver siRNA efficiently to tumours after intravenous administration. Using these particles, around 50% knockdown of the target gene expression was observed in tumours. With the use of siRNA targeting the E6/7 oncogenes expressed in cervical cancer, we showed a 50% reduction in tumour size. This level of tumour growth suppression was comparable to that achieved from cisplatin at the clinically used dose. Overall, our results demonstrate the feasibility of using HFDM-formulated particles to systematically administer E6/7-targeted siRNA for cervical cancer treatment. The simplicity of preparation procedure along with superior product stability obtained from our method offers an innovative approach for the in vivo delivery of siRNA.

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Stability of siRNA polyplexes from poly(ethylenimine) and poly(ethylenimine)-g-poly(ethylene glycol) under in vivo conditions: Effects on pharmacokinetics and biodistribution measured by Fluorescence Fluctuation Spectroscopy and Single Photon Emission Computed Tomography (SPECT) imaging

Cited by 170 publications

References 53 publications

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Polycation-siRNA nanoparticles can disassemble at the kidney glomerular basement membrane

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Systemic delivery of E6/7 siRNA using novel lipidic particles and its application with cisplatin in cervical cancer mouse models

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